Abstract
BackgroundThe T cell Ig domain and mucin domain (TIM)-1 protein expressed on the surface of Th2 cells regulates the immune response by modulating cytokine production. The present study aimed to investigate the role and possible mechanism of TIM-1 in cerebral ischemia-reperfusion injury.MethodsWestern blot was used to detect TIM-1 and apoptosis-related protein expression, whereas TIM-1 mRNA was examined using quantitative real-time reverse transcription PCR. Flow cytometry and a TdT-mediated biotin-16-dUTP nick-end labeling (TUNEL) assay were used to detect the percentage of apoptotic cells and a pathological examination was performed. The migration of neutrophils and macrophages was analyzed by immunohistochemistry.ResultsOur results suggest that TIM-1 expression was transiently increased 24 h or 48 h following middle cerebral artery occlusion (MCAO)/reperfusion. The infarct size was markedly increased in MCAO, whereas treatment with a TIM-1-blocking mAb could reduce the infarct size. TIM-1 blocking mAb effectively reduced the number of neutrophils, macrophage functionality, cytokine (i.e., IL-6, IL-1β, and TNF-α) and chemokine (i.e., CXCL-1 and CXCL-2) production in the brain tissue. The effect of in vitro T cell damage on neurons was significantly reduced following treatment with a TIM-1 blocking mAb or the knockdown of TIM-1 in co-cultured T cells and neurons.ConclusionTake together, these results indicated that TIM-1 blockade ameliorated cerebral ischemia-reperfusion injury. Thus, TIM-1 disruption may serve as a novel target for therapy following MCAO.
Highlights
The T cell Ig domain and mucin domain (TIM)-1 protein expressed on the surface of T-helper 2 (Th2) cells regulates the immune response by modulating cytokine production
T cell immunoglobulin and mucin domain (TIM)-1 expression was upregulated in middle cerebral artery occlusion (MCAO) To determine the effect of TIM-1 on the MCAO, we detected the level of TIM-1 mRNA and protein expression after MCAO at 24 h and 48 h by qRT-PCR and Western blot
The results found that the expression of TIM-1 mRNA and protein was significantly upregulated 24 h and 48 h after MCAO; the longer the MACO time (48 h), the higher the expression of TIM-1 (Fig. 1ac)
Summary
The T cell Ig domain and mucin domain (TIM)-1 protein expressed on the surface of Th2 cells regulates the immune response by modulating cytokine production. The present study aimed to investigate the role and possible mechanism of TIM-1 in cerebral ischemia-reperfusion injury. During the acute phase of ischemic reperfusion (I/R) injury, there are multiple waves of cellular infiltration, consisting of macrophages, neutrophils, and lymphocytes [8]. The family of T cell immunoglobulin and mucin domain (TIM) proteins are type 1 transmembrane proteins, including eight mouse proteins (TIM-1 TIM-8) and three members (TIM-1, TIM-3, and TIM-4) in humans are expressed on various immune cells and can mediate coinhibitory and costimulatory signals [10, 11]. T lymphocytes are key contributors to the acute phase of cerebral ischemia reperfusion injury, the relevant T cell-derived mediators of tissue injury remain unknown. Using an antagonistic anti-TIM monoclonal antibody (mAb) [14], it was shown that a TIM-1 blockade prolongs allograft survival by downregulating Th1 cells and promoting Th2-mediated alloresponses [15]; no reports have studied the role of TIM-1 in stroke
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